Program 1: Metabolism, Genetics, Immunity & Environment
This program is coordinated by Pr. Guido Kroemer and Pr. Jessica Zucman-Rossi
Major theme of the program
The present research program will explore epidemiological relationships between major signs of aberrant metabolism (overweight, obesity, vitamin deficiencies, metabolic syndrome, diabetes…) to the incidence, molecular subtype, outcome and therapeutic response of several major cancers, while focusing on mammary carcinoma, colorectal cancer, non-small-cell lung cancer and hepatocellular carcinoma). Such epidemiological links will be hypothesis-generating to investigate the possible cause-effect relationship between metabolic alterations at the whole-body level and cancer development in suitable mouse models and to perform interventional clinical trials (diet + exercise + treatment of obesity-related co-morbidities) on cancer patients
Beyond whole-body metabolism, the consortium will investigate the metabolic alterations affecting isolated cancer cells (oncometabolism), isolated immune cells (immunometabolism) as well as the entire tumor micro-ecosystem (tumor metabolism), obviously with the ultimate goal to identify new biomarkers for risk stratification and novel therapeutic targets for cancer treatment.
The CARPEM consortium has a long-standing experience in the area of immuno-oncology, meaning that the metabolic exploration will take into account the major role that the immune system plays in determining the therapeutic response of cancer patients to conventional therapies (chemotherapy, radiotherapy), targeted therapies and immunotherapy.
Why this specific theme?
Cancer has historically been conceived as a cell-autonomous genetic (and epigenetic) disease, meaning that major focus has been placed on the genomic exploration of malignant cells. The recent success of immune checkpoint blockers has led to the integration of immunological parameters in the characterization and classification of cancers as well.
CARPEM has been extremely active in this flourishing area, contributing to major insights into the exploration of the immune infiltrate at cancer diagnosis [Fridman Nat Rev Clin Oncol 2017], and also at its modulation by therapeutic agents [Galluzzi Cancer Cell 2015, Pietrocola Cancer Cell 2016].
In addition, several CARPEM-associated research teams have a major expertise in biochemistry and metabolism [Zitvogel Nature Immunology 2017, Routy Science 2017, Madeo Science 2017; Gougelet Hepatology 2014, Levy Nat Cell Biol 2015, Schulze Nature Genet 2015], offering the possibility to add a metabolic dimension to the merely bidimensional vision (cancer genetics versus immunity) that currently dominates cancer research. This will create a tridimensional space in which the effects of metabolism may be investigated at several complementary levels, in cancer cells (oncometabolism), in immune cells (immunometabolism), in the entire tumor with all its stromal elements (tumor metabolism), and at the whole-body level (general metabolism).
Obviously, whole-body metabolism is profoundly influenced by life style factors (namely the quantity and quality of nutrition and physical activity), allowing the functional and epidemiological exploration of major risk factors of malignant disease (such as obesity, sedentary life style, metabolic syndrome and diabetes).
As a result, CARPEM has chosen to enter the era of post-genomics by taking advantage of a unique constellation, namely,
- the inclusion of several world class teams with metabolic expertise
- the fact that several CARPEM teams are focusing on cancer types for which obesity or imbalanced nutrition are major risk factor, as this applies to as liver, colorectal and breast cancer.
General background and medical needs
There is no doubt that obesity will eventually become the first avoidable risk factor for cancer, before tobacco. Nonetheless, the molecular comprehension of this epidemiological link is in its infancy, requiring in-depth investigation in several major cancers (in particular, breast, colorectal and hepatocellular cancer). For instance, it will be important to understand which genetically or immunologically defined subtypes of cancer are associated with particular metabolic aberrations. Although it has been generally assumed that major aberrations in metabolism (due to caloric excess, poor quality of nutrition, ingestion of toxins, alterations of the gut microbiota, absence of physical activity etc.) may cause oncogenesis and tumor progression via cell-autonomous effects, it has become increasingly clear that metabolic alterations may impact on cancer via indirect, leukocyte-dependent effects, namely, chronic, pro-carcinogenic inflammation as well as reduced anticancer immunosurveillance [Zitvogel Nature Immunology 2017].
The discovery of metabolic aberrations within cancers may yield new actionable targets in the area of immuno-oncology. For example, autophagy, which has major roles in metabolism [Galluzzi Cell 2014] can be targeted for tumor therapy [Galluzzi EMBO J 2016]. Suppressed autophagy is a general feature of obesity and old age [Lopez-Otin Cell 2016]. CARPEM-associated teams have demonstrated that autophagy-deficient mouse cancers fail to elicit an anticancer immune response in the context of chemotherapy or radiotherapy [Michaud Science 2011, Galluzzi Nat Rev Clin Oncol 2017] and that, in human breast cancers, treated with adjuvant chemotherapy, defective autophagy is associated with poor immunosurveillance, as indicated by a poor CD8/FOXP3 ratio [Kroemer Nature Med 2015, Ladoire Autophagy 2016]. Hence strategies may be developed to induce autophagy by fasting or novel pharmacological agents [Galluzzi Nat Rev Drug Discov 2017] with the scope of stimulating the anticancer immune response [Pietrocola Cancer Cell 2016]. In contrast, in colorectal cancer autophagy inhibition might be envisaged to prevent onocogenesis [Levy Nat Cell Biol 2015].
The CARPEM consortium also discovered that pyridoxine (vitamin B6) can stimulate anticancer immune responses in the context of cisplatin-treated orthotopic mouse non-small cell lung cancers (NSCLC) [Aranda Oncogene 2015]. In human NSCLC, low levels of pyridoxal kinase (PDXK) expression by neoplastic cells correlates with a weak infiltration by DC-LAMP+ dendritic cells (DC) and indicates poor prognosis [Galluzzi Cell Report 2012]. Moreover, high levels of poly adenosine ribosyl (PAR) adducts produced by PAR polymerase-1 (PARP) correlate with weak infiltration by CD8+ cytotoxic T lymphocytes (CTL) in human NSCLC, and both elevated PAR levels and low infiltration by CTL indicate poor prognosis [Michels et al. 2014 Cancer Research; Michels et al. 2016 Annals Oncology; Fridman Nat Rev Clin Oncol 2017]. This suggests the possibility to use PARP inhibitors as immunomodulators in specific circumstances.
CARPEM will continue these lines of investigation with the quadruple objective to:
- establish new, more precise associations between metabolic features and molecular/immunological cancer subtypes,
- investigate new cause-effect relationships between dysmetabolism and oncogenesis, tumor progression, failure of immunosurveillance and therapy resistance,
- establish novel biomarkers for risk stratification in major cancer types, and
- identify molecular targets that may constitute intervention points for the clinical and pharmacological management of cancer patients.
Main objectives of the program
Our project is subdivided in two work packages (WP), namely:
WP1: “Decipher the fundamental role of metabolism in cell transformation, immunosurveillance and therapeutic intervention”
WP1 will deal with the clinical connections between oncometabolism and immunosurveillance (Task 1),
WP1 will also explore the connections between whole-body metabolism and immunosurveillance (Task 2).
WP1 also deals with strictly epidemiological/clinical observations (Task 3) aiming at determining new associations between metabolic and oncological parameters by informatics “big data” analyses and by performing clinical trials in which nutrition and/or physical activity will be targeted with the scope of ameliorating the treatment of major cancers.
WP2: “Metabolism, genetics, immunity and environment in digestive cancers”
WP2 will focus on the clinical connections between cancer cell genetics, immunity, metabolism and environment in digestive cancers (mostly colorectal and hepatocellular carcinoma, but also to some extent in pancreatic cancer).
With respect to liver cancer (Task 1), WP2 will deal with the important question as to whether metabolic syndrome, diabetes, obesity and non-alcoholic steatohepatitis (NASH) affect the risk of developing liver cancer of particular molecular subtypes.
With respect to colorectal cancer (Task 2), WP2 will address the question as to whether obesity and/or metabolic syndrome will affect the mutational pattern, the particular molecular subtype and the “immunoscore”
Clearly, the integrated research program 1 is connected to program 2, because the in-depth characterization of the immune infiltrate (by advanced cytometry and single-cell sequencing) developed in program 2 will furnish invaluable information on the status of immunosurveillance that can be taken advantage of to study metabolic connections at a level of unprecedented refinement. The integrated research program 1 is also conneted to program 3 by the need to use the dynamic consent.